CN115364216B - Two-dimensional metal carbide nanocomposite and preparation method and application thereof - Google Patents
Two-dimensional metal carbide nanocomposite and preparation method and application thereof Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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- A61P39/06—Free radical scavengers or antioxidants
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- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
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Abstract
The invention provides a two-dimensional metal carbide nanocomposite, a preparation method and application thereof, wherein the method comprises the following steps: s1, adding two-dimensional metal carbide powder into a stripping solvent, carrying out ultrasonic stripping under ice water bath, centrifuging, collecting supernatant, and freeze-drying to obtain two-dimensional metal carbide nano-dots; s2, dispersing the two-dimensional transition metal carbide nano points in ethanol, adding PVP for premixing, stirring and refluxing at 70-90 ℃ for 8-24 hours, and centrifuging to obtain the PVP modified two-dimensional metal carbide nano composite material. The method utilizes an ultrasonic liquid phase stripping method to prepare the ultra-small zirconium carbide nano-dots with excellent photo-thermal performance and good ROS scavenging capability, and further surface modification is carried out to improve the stability of the material, so that the novel photo-thermal nano-material with good water dispersibility, low toxicity and non-inflammatory property is finally obtained, and is used for the non-inflammatory photo-thermal treatment of tumors.
Description
Technical Field
The invention relates to the technical field of preparation of two-dimensional metal carbide nano composite materials and non-inflammatory photothermal treatment of tumors, in particular to a PVP modified two-dimensional metal carbide nano composite material and a preparation method and application thereof.
Background
Photothermal therapy (PTT) is a hyperthermia method that uses photothermal conversion agents (PTCAs) to generate sufficient heat under near infrared (NIR, 700-1100 nm) light to ablate solid tumors. PTT, as a non-invasive hyperthermia method, has its unique advantages over traditional tumor treatment methods: (1) healthy normal tissue is minimally damaged; (2) non-invasive or minimally invasive; (3) effective anticancer activity; etc. PTT has attracted considerable attention from researchers because of the excellent advantages exhibited.
In general, the total extinction coefficient of near infrared light is relatively low relative to other light components, and penetrates deeper into tissue than Ultraviolet (UV) or visible light. Thus, the penetration depth of near infrared light can be optimized for a variety of cancers, resulting in efficient tumor treatment. However, while tumors can be rapidly resected by photothermal therapy, the large amounts of Reactive Oxygen Species (ROS) that accompany release can trigger negative inflammatory reactions, thereby compromising the effectiveness of such treatment. Over the last several decades, many studies have demonstrated that an important link between inflammation and cancer increases the risk of cancer in persons suffering from chronic inflammation by about 20%. It is thought that PTT-induced inflammation may promote metastasis and worsen prognosis of tumors, as inflammation may provide a cancerous-like condition for epithelial-to-mesenchymal transition (EMT), tumor recurrence and metastasis. In addition, inflammation is often accompanied by tissue damage, slowing wound healing, and causing severe pain to the patient. Therefore, development of PTCAs for photothermal ablation of non-inflammatory/anti-inflammatory tumors is central to photothermal therapy. However, few reports on this topic are available.
Currently, factors affecting the performance of PTCAs mainly include absorption wavelength, size, material and shape and surface modification, etc., which all affect the absorption wavelength and size of PTCAs. However, the larger the size of PTCAs, the higher the light-heat conversion efficiency is, but there are drawbacks in that the penetration is reduced and the toxicity of foreign matters is higher, resulting in limited use thereof. The size of the PTCAs nanoparticles used at present is generally between 50 and 300 nm.
We have found in the course of developing PTCAs for non-inflammatory/anti-inflammatory tumor photothermal ablation that transition metal carbides Ti 3 C 2 Is very good inThe promising photo-thermal conversion material has good photo-thermal conversion efficiency, and the extinction coefficient of 808nm is 7.39Lg -1 cm -1 . Zirconium (Zr), however, is of the same family as Ti but with a larger period, can be used to optimize the thermal plasma effect due to its external heavy atoms. Experimental study shows that the extinction coefficient ratio Ti of the zirconium carbide nano-dots at 808nm 3 C 2 The ultrafine zirconium carbide nano-dot has high biological safety and can be rapidly metabolized and discharged from the body. Therefore, the prepared zirconium carbide nano-dots can be used as a new PTCAs for photothermal therapy, but the prepared zirconium carbide nano-dots have the phenomenon of unstable dispersion in aqueous solution. Thus, there is a need for improvements in zirconium carbide nanodots to obtain PTCAs that are dispersible and stable in aqueous solutions.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a PVP modified two-dimensional metal carbide nanocomposite, and a preparation method and application thereof. The method provided by the invention utilizes an ultrasonic liquid phase stripping method to prepare the ultra-small zirconium carbide nano-dots with excellent photo-thermal properties and good ROS scavenging capability, and further improves the stability of the material through further surface modification, so that the novel photo-thermal nano-material with good water dispersibility, low toxicity and non-inflammatory property is finally obtained, and is used for the non-inflammatory photo-thermal treatment of tumors.
In order to achieve the above object, the technical scheme of the present invention is as follows.
A method for preparing a two-dimensional metal carbide nanocomposite, comprising the steps of:
s1, adding two-dimensional metal carbide powder into a stripping solvent, carrying out ultrasonic stripping under ice water bath, centrifuging, collecting supernatant, and freeze-drying to obtain two-dimensional metal carbide nano-dots;
s2, dispersing the two-dimensional transition metal carbide nano points in ethanol, adding PVP for premixing, stirring and refluxing at 70-90 ℃ for 8-24 hours, and centrifuging to obtain the PVP modified two-dimensional metal carbide nano composite material.
In S1, the stripping solvent is N-methylpyrrolidone.
Further, in S1, the two-dimensional transition metal carbide is zirconium carbide.
Further, in S1, the use amount ratio of the two-dimensional transition metal carbide powder to the stripping solvent was 1g: 10-30 mL.
Further, in S1, the power of ultrasonic peeling is 300W; the ultrasonic stripping time is 1-3 h.
In S1, ultrasonic dispersion is further included after ultrasonic stripping, the power of ultrasonic dispersion is 300-800W, and the time of ultrasonic dispersion is 24-48 h.
Further, in S2, the dosage ratio of the two-dimensional transition metal carbide nanodots to ethanol and PVP is 500mg: 10-30 mL: 2-5 g.
The invention provides a two-dimensional metal carbide nanocomposite prepared by the method.
The invention also provides application of the two-dimensional metal carbide nanocomposite in preparing a tumor non-inflammatory photothermal therapeutic drug.
Further, the two-dimensional metal carbide nanocomposite is dispersed in water to prepare a solution having a concentration of 1 to 2 mg/mL.
The invention also provides application of the two-dimensional metal carbide nanocomposite in preparing a photosensitizer with oxygen free radical scavenging capability.
The invention has the beneficial effects that:
1. the invention takes commercial zirconium carbide as a raw material, adopts an ultrasonic liquid phase stripping method to prepare the zirconium carbide nano-dots (ZrC NDs) with good stability and water solubility, and prepares the zirconium carbide nano-material (PVP-ZrC NDs) with good photo-thermal performance by modifying the zirconium carbide nano-dots with polyvinylpyrrolidone (PVP). The PVP-ZrC NDs obtained by the method have good oxygen free radical scavenging capability, are fast in metabolism, have anti-inflammatory property, can reduce inflammatory reaction induced by photo-heat per se during photo-heat treatment, overcome the defect of inflammatory reaction induced by traditional photo-heat treatment, and provide a safe and effective scheme for non-inflammatory photo-heat treatment of glioma.
2. The method adopts an ultrasonic liquid phase stripping method to synthesize and prepare the novel non-inflammatory photo-thermal PVP-ZrC NDs with low cost, high stability and easy preservation. The ultra-small PVP-ZrC NDs have excellent photothermal conversion efficiency (extinction coefficient of 12.1Lg at 808 nm) -1 cm -1 Other reported extinction coefficients for photothermal materials are: titanium carbide 7.39Lg -1 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the Graphene oxide nanoplatelets 3.6Lg -1 cm -1 ；Ti 3 C 2 -Fe 3 O 4 ：7.9Lg -1 cm -1 ). The material has good oxygen free radical and nitrogen free radical scavenging activity, eliminates inflammation generation caused by a large amount of free radicals induced by light and heat, provides a new treatment thought for photothermal treatment, has good biological safety, and can be rapidly excreted by metabolism.
3. The preparation process is simple, the raw materials are low in cost, and the preparation method can be used for mass preparation; and can be dispersed and stabilized in aqueous solution after simple surface modification; the prepared nano composite material has good photo-thermal effect and low cytotoxicity, and has potential of clinical transformation application.
Drawings
Fig. 1 is a schematic diagram of a preparation process and a potential biological mechanism of a two-dimensional metal carbide nanocomposite provided by the invention.
FIG. 2 is a high resolution transmission electron microscope image, diffraction pattern and particle size distribution diagram of PVP-ZrC NDs obtained in example 1. Wherein, FIG. 2a is a high resolution transmission electron microscope image; FIG. 2b is a diffraction pattern; FIG. 2c is a particle size distribution plot.
FIG. 3 is an ultraviolet-visible absorption spectrum and an extinction coefficient fitting chart of PVP-ZrC NDs obtained in example 1. Wherein FIG. 3 (a) is an ultraviolet-visible light absorption test chart of solutions of different concentrations; fig. 3 (b) is a linear fitting diagram.
FIG. 4 is a graph showing the effect of heating up PVP-ZrC NDs obtained in example 1 under 808nm laser irradiation and a graph showing photo-thermal stability. FIG. 4 (a) is a graph showing the effect of PVP-ZrC NDs solutions of different concentrations on irradiation for a period of timeInter-temperature change curve. FIG. 4 (b) is a photo-thermal stability test chart of PVP-ZrC NDs of example 1 after 5 heating/cooling cycles. FIG. 4 (c) shows the laser irradiation of PVP-ZrC NDs solutions of different concentrations at 808nm (1.0W/cm 2 ) Photothermal image under, and irradiation with different laser powers (0.5W/cm 2 、1.5W/cm 2 ) And (3) a photothermal image.
FIG. 5 is a fluorescence image of the photothermal therapeutic effect of PVP-ZrC NDs obtained in example 1 on GL261 glioma cells by different treatments. Wherein PI represents treatment with propidium iodide (red, dead cells); calcein-AM means treatment with Calcein (green, living cells); merge denotes treatment with calcein in combination with propidium iodide (red as dead cells, green as viable cells); NIR means 808nm laser irradiation; PBS represents a PBS buffer control group; zrC represents PVP-ZrC NDs before laser irradiation; zrC+NIR 5min represents PVP-ZrC NDs 808nm laser irradiation for 5min; zrC+NIR 8min represents PVP-ZrC NDs 808nm laser irradiation for 8min; zrC+NIR 10min represents PVP-ZrC NDs 808nm laser irradiation for 10min.
FIG. 6 is a graph showing the effect of PVP-ZrC NDs obtained in example 1 on scavenging active oxygen and anti-inflammatory (classical inflammatory factors: IL-1β, IL-6, TNF- α) effects. FIG. 6 (a) is a graph of wavelength versus absorbance for samples of different concentrations; FIG. 6 (b) is a concentration-inhibition bar graph of samples of different concentrations. FIG. 6 (c) is a graph showing the absorbance of the DPPH at various concentrations. FIG. 6 (d) is a bar graph showing the change in levels of inflammatory factor TNF-. Alpha.in different treatment groups. FIG. 6 (e) is a bar graph showing the change in the level of inflammatory factor IL-1β in different treatment groups. FIG. 6 (f) is a bar graph showing the change in the levels of inflammatory factor IL-6 in different treatment groups. Wherein control is a blank control group; LPS is LPS group; GO+LPS is the LPS-induced validated model cells co-cultured with PVP-GONDs of comparative example 2; zrC+LPS is a validated model cell induced by LPS and PVP-ZrC NDs co-cultured group of example 1.
FIG. 7 is a graph showing the effect of PVP-ZrC NDs obtained in example 1 on the treatment of glioma in mice transplanted subcutaneously FIG. 7 (a) is a representative photograph of tumors of mice from different treatment groups at the end; FIG. 7 (b) is a bar graph of the weight change of resected tumor after treatment of each treatment group; FIG. 7 (c) is a graph showing the change in average tumor volume after 808nm laser irradiation in each treatment group. Wherein, contrl is a blank control (PBS) group; NIR 808nm laser group; zrC is PVP-ZrC NDs solution injected by tail vein; zrC+NIR is a tumor group irradiated with laser at 808nm after PVP-ZrC NDs solution is injected through tail vein.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
Example 1
Referring to fig. 1, a method for preparing a two-dimensional metal carbide nanocomposite material includes the following steps:
s1, adding 1.0g of commercial zirconium carbide (ZrC) powder into a glass bottle containing 20mL of N-methylpyrrolidone (NMP), and then placing the glass bottle containing ZrC into an ice water bath (0 ℃) environment, and carrying out ultrasonic stripping for 2 hours under the power of 300W by using an ultrasonic probe. The vial was then transferred to an ultrasonic sink and sonicated in an ultrasonic water bath at 300W power for a further 30h.
After the ultrasonic treatment, filtering, respectively washing the precipitate with absolute ethyl alcohol and deionized water, merging the filtrates, centrifuging for 20min at 8000 rpm by using a centrifuge, taking supernatant, and freeze-drying in a vacuum freeze-dryer to obtain the powder which is zirconium carbide nano-dots (ZrC NDs).
S2, dispersing 500mg of zirconium carbide nano-dot sample in 20mL absolute ethanol, adding 2.5g of PVP for premixing, and stirring and refluxing in an oil bath at 80 ℃ for 12h. And centrifuging the solution, washing the precipitate with deionized water and ethanol, and continuing centrifuging to obtain the PVP modified two-dimensional metal carbide nanocomposite (PVP-ZrC NDs) powder.
Example 2
Referring to fig. 1, a method for preparing a two-dimensional metal carbide nanocomposite material includes the following steps:
s1, adding 1.0g of commercial zirconium carbide (ZrC) powder into a glass bottle containing 10mL of N-methylpyrrolidone (NMP), and then placing the glass bottle containing ZrC into an ice water bath (0 ℃) environment, and carrying out ultrasonic stripping for 1h under the power of 300W by using an ultrasonic probe. The vials were then transferred to an ultrasonic sink and sonicated in an ultrasonic water bath at 300W power for a further 24 hours.
After the ultrasonic treatment, filtering, respectively washing the precipitate with absolute ethyl alcohol and deionized water, merging the filtrates, centrifuging for 20min at 8000 rpm by using a centrifuge, taking supernatant, and freeze-drying in a vacuum freeze-dryer to obtain the powder which is zirconium carbide nano-dots (ZrC NDs).
S2, dispersing 500mg of zirconium carbide nano-dot sample in 10mL absolute ethanol, adding 2g of PVP for premixing, and stirring and refluxing in an oil bath at 70 ℃ for 24h. And centrifuging the solution, washing the precipitate with deionized water and ethanol, and continuing centrifuging to obtain the PVP modified two-dimensional metal carbide nanocomposite (PVP-ZrC NDs) powder.
Example 3
Referring to fig. 1, a method for preparing a two-dimensional metal carbide nanocomposite material includes the following steps:
s1, adding 1.0g of commercial zirconium carbide (ZrC) powder into a glass bottle containing 30mL of N-methylpyrrolidone (NMP), and then placing the glass bottle containing ZrC into an ice water bath (0 ℃) environment, and carrying out ultrasonic stripping for 3 hours under the power of 300W by using an ultrasonic probe. The vial was then transferred to an ultrasonic sink and sonicated in an ultrasonic water bath at 300W power for a further 48 hours.
After the ultrasonic treatment, filtering, respectively washing the precipitate with absolute ethyl alcohol and deionized water, merging the filtrates, centrifuging for 20min at 8000 rpm by using a centrifuge, taking supernatant, and freeze-drying in a vacuum freeze-dryer to obtain the powder which is zirconium carbide nano-dots (ZrC NDs).
S2, dispersing 500mg of zirconium carbide nano-dot sample in 30mL absolute ethanol, adding 5g of PVP for premixing, and stirring and refluxing in an oil bath at 90 ℃ for 8h. And centrifuging the solution, washing the precipitate with deionized water and ethanol, and continuing centrifuging to obtain the PVP modified two-dimensional metal carbide nanocomposite (PVP-ZrC NDs) powder.
Comparative example 1
A method for preparing a two-dimensional metal carbide nanocomposite, substantially the same as in example 1, except that:
with titanium carbide (Ti) 3 C 2 ) The powder replaces zirconium carbide (ZrC) powder.
Comparative example 2
A method for preparing a two-dimensional metal carbide nanocomposite, substantially the same as in example 1, except that:
replacing zirconium carbide (ZrC) powder with graphene oxide nanoplatelet (GO) powder.
Comparative example 3
A method for preparing a two-dimensional metal carbide nanocomposite, substantially the same as in example 1, except that:
with Ti 3 C 2 -Fe 3 O 4 The powder replaces zirconium carbide (ZrC) powder.
The PVP-ZrC NDs obtained in examples 1 to 3 were substantially identical in performance, and thus morphology analysis, ultraviolet and visible light absorption test, temperature rising efficiency test, photo-thermal stability test, in vitro tumor killing ability test, free radical scavenging ability test, and photo-thermal ablation test of solid tumors of mice were performed only with PVP-ZrC NDs obtained in example 1.
1. Morphology analysis of zirconium carbide nanodots
The PVP-ZrC NDs obtained in example 1 were subjected to morphological analysis, and the specific results are shown in FIG. 2. Wherein, FIG. 2a is a high resolution transmission electron microscope image; FIG. 2b is a diffraction pattern; FIG. 2c is a particle size distribution plot.
From fig. 2a, it can be seen that the nanoparticles are uniformly distributed and the particle size is relatively uniform; from the particle size distribution statistics (FIG. 2 c), it can be seen that the particle size of PVP-ZrC NDs is mainly concentrated in the range of 4 to 5nm, and the average particle size is about 4.5 nm. As can be seen from fig. 2b, a PVP layer was formed on the surface of ZrC NDs, which further demonstrates that PVP-modified zirconium carbide nanodots (PVP-ZrC NDs) were successfully prepared in example 1 of the present invention.
2. Ultraviolet-visible light absorption test
PVP-ZrC NDs obtained in example 1 were dispersed in water to prepare solutions having gradient concentrations of 10, 20, 30, 40, 50, 60. Mu.g/mL, and UV-visible light absorption tests were performed in a UV spectrophotometer, respectively, and then linear fitting was performed to calculate extinction coefficients, and the results are shown in FIG. 3. FIG. 3 (a) is a graph showing UV-visible absorption test of solutions of different concentrations; fig. 3 (b) is a linear fitting diagram.
As can be seen from the results of fig. 3, the linear regression equation is obtained by performing a linear fit with different concentrations x as abscissa and absorbance y as ordinate: y=0.0122+0.067, r 2 =0.99. Thus, according to beer's law a=epsilonbc, where a is absorbance and epsilon is the extinction coefficient; b is the optical path length (cm); c is the concentration of the light absorbing substance (g/L).
Calculated, the extinction coefficient epsilon of PVP-ZrC NDs prepared in the embodiment 1 of the invention at 808nm wavelength 808 ＝12.1Lg -1 cm -1 。
PVP-Ti of comparative example 1 3 C 2 Extinction coefficient epsilon of NDs at 808nm wavelength 808 ＝7.39Lg -1 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the Comparative example 2 extinction coefficient ε of PVP-graphene oxide nanoplatelets NDs at 808nm wavelength 808 ＝3.6Lg -1 cm -1 The method comprises the steps of carrying out a first treatment on the surface of the Comparative example 3 PVP-Ti 3 C 2 -Fe 3 O 4 Extinction coefficient epsilon of NDs at 808nm wavelength 808 ＝7.9Lg -1 cm -1 。
As is clear from comparison of comparative examples 1 to 3, the extinction coefficient of PVP-ZrC NDs prepared from ZrC powder in example 1 of the present invention at 808nm wavelength is larger, which indicates that the ultra-small PVP-ZrC NDs has more excellent photo-thermal conversion efficiency.
3. In vitro evaluation of photothermal Effect
In order to further evaluate the photo-thermal effect of PVP-ZrC NDs on tumors in vivo, PVP-ZrC NDs obtained in example 1 of the present invention were prepared into solutions with gradient concentrations of 0, 10, 15, 20, 30 and 40. Mu.g/mL, and the photo-thermal stability was tested by monitoring the heating effect and photographing in real time using an infrared camera under the irradiation of 808nm laser, and the results are shown in FIG. 4. FIGS. 4 (a) and 4 (c) are graphs showing the effect of temperature increase by 808nm laser irradiation; the right panel of fig. 4 (b) is a photo-thermal stability diagram.
FIG. 4 (a) is a time-temperature profile of PVP-ZrC NDs solutions of different concentrations over a period of irradiation. As can be seen from FIG. 4 (a), the temperature of the 40. Mu.g/mL solution sample of PVP-ZrC NDs was rapidly increased from 25℃to 53℃within 300 seconds of irradiation, and reached a maximum temperature of 57.5℃after 600 seconds of irradiation. FIG. 4 (c) shows the laser irradiation of PVP-ZrC NDs solutions of different concentrations at 808nm (1.0W/cm 2 ) Photothermal image under, and irradiation with different laser powers (0.5W/cm 2 、1.5W/cm 2 ) And (3) a photothermal image. The results of fig. 4 (a) and fig. 4 (c) show that the PVP-ZrC NDs of the embodiment of the invention have good heating efficiency, and the heating effect is positively correlated with the laser power. FIG. 4 (b) is a photo-thermal stability test chart of PVP-ZrC NDs of example 1 after 5 heating/cooling cycles. As shown in FIG. 4 (b), the PVP-ZrC NDs of example 1 showed substantially no change in the photo-thermal conversion behavior after 5 heating/cooling cycles, thereby demonstrating that the PVP-ZrC NDs of example 1 had excellent photo-thermal stability before and after laser irradiation. This further verifies that PVP-ZrC NDs of example 1 of the present invention have excellent photothermal therapeutic capabilities and can be used as potential photothermal conversion agents.
4. In vitro tumor killing capability test
PVP-ZrC NDs obtained in example 1 were prepared as a solution having a concentration of 100. Mu.g/mL, and the solution was tested for its in vitro tumor killing ability. The above solution was co-cultured with GL261 glioma cells for 24 hours, then after laser irradiation at 808nm for 0min, 5min, 8min, 10min, cultured overnight, then washed three times with PBS, and added with Calcein-AM, propidium Iodide (PI) or Merge (combined treatment of Calcein and propidium iodide), respectively, to perform dead/living staining of the cells, the dead cells appeared red, the living cells appeared green, observation by a fluorescence microscope and photographing, and the results are shown in FIG. 5. FIG. 5 is a fluorescence image of the photothermal therapeutic effect of PVP-ZrC NDs obtained in example 1 on GL261 glioma cells by different treatments. Wherein PI represents treatment with propidium iodide (red, dead cells); calcein-AM means treatment with Calcein (green, living cells); merge denotes treatment with calcein in combination with propidium iodide (red as dead cells, green as viable cells); NIR means 808nm laser irradiation; PBS represents a PBS buffer control group; zrC represents PVP-ZrC NDs before laser irradiation; zrC+NIR 5min represents PVP-ZrC NDs 808nm laser irradiation for 5min; zrC+NIR 8min represents PVP-ZrC NDs 808nm laser irradiation for 8min; zrC+NIR 10min represents PVP-ZrC NDs 808nm laser irradiation for 10min.
As can be seen from fig. 5, PBS group and Zrc group showed significant green fluorescence, indicating that PVP-ZrC NDs had low toxicity to GL261 glioma cells, and no significant in vivo toxicity. Cells in the zrc+nir 5min group, zrc+nir 8min group and zrc+nir 10min group showed clear red fluorescence compared to Zrc group, indicating that photothermal treatment can cause extensive GL261 glioma cell death and has superior tumor cell killing effect. Therefore, the PVP-ZrC NDs obtained in the embodiment 1 have good photo-thermal killing effect on tumor cells and have good application prospect on photo-thermal treatment of tumors.
5. Free radical scavenging ability test
The PVP-ZrC NDs obtained in example 1 were prepared into solutions having concentrations of 0, 5, 10, 15, 20, 25, 50, 100, 150, 200. Mu.g/mL, and tested for radical scavenging ability.
The ROS kit is adopted to detect the level of active oxygen, and the ABTS probe and the DPPH probe are adopted to detect the scavenging ability of oxygen free radicals and nitrogen free radicals.
Normal human vascular endothelial cells are stimulated by LPS (lipopolysaccharide) to serve as an inflammatory activating cell model, PVP surface modified zirconium carbide nanodot solution is incubated for co-culture, and qPCR (quantitative polymerase chain reaction) is used for detecting the gene level expression index of inflammatory factors, and the result is shown in figure 6. FIG. 6 is a graph showing the effect of PVP-ZrC NDs obtained in example 1 on scavenging active oxygen and anti-inflammatory (classical inflammatory factors: IL-1β, IL-6, TNF- α) effects.
Wherein, IL-1 beta is interleukin 1 beta; IL-6 is interleukin 6; TNF-alpha is tumor necrosis factor-alpha.
FIG. 6 (a) is a graph of wavelength versus absorbance for samples of different concentrations; FIG. 6 (b) is a concentration-inhibition bar graph of samples of different concentrations. FIG. 6 (c) is a graph showing the absorbance of the DPPH at various concentrations. FIG. 6 (d) is a bar graph showing the change in levels of inflammatory factor TNF-. Alpha.in different treatment groups. FIG. 6 (e) is a bar graph showing the change in the level of inflammatory factor IL-1β in different treatment groups. FIG. 6 (f) is a bar graph showing the change in the levels of inflammatory factor IL-6 in different treatment groups. Wherein control is a blank control group; LPS is LPS group; GO+LPS is the LPS-induced validated model cells co-cultured with PVP-GONDs of comparative example 2; zrC+LPS is a validated model cell induced by LPS and PVP-ZrC NDs co-cultured group of example 1.
From FIGS. 6 (a) to 6 (c), it can be seen that PVP-ZrC NDs of example 1 of the present invention have excellent free radical scavenging ability, and the concentration of the solution is proportional to the scavenging effect. As can be seen from fig. 6 (d) to 6 (f), the zrc+lps group exhibited a stronger anti-inflammatory ability than the go+lps group. This demonstrates that PVP-ZrC NDs obtained in example 1 have free radical scavenging and anti-inflammatory capabilities.
6. Photo-thermal ablation test for solid tumors of mice
To further verify the in vitro therapeutic effect of PVP-ZrC NDs. PVP-ZrC NDs obtained in example 1 was prepared as a solution having a concentration of 2mg/mL, and then tumor-bearing mice (100. Mu.L) were injected into the tail vein, and after 12 hours, tumor-bearing mice were continuously observed for 2 weeks by irradiating the tumor-bearing mice with a laser at 808nm for 5 minutes, and tumor changes were recorded. After 2 weeks, the tumor was removed, observed and photographed, and the results are shown in fig. 7. FIG. 7 is a graph showing the effect of PVP-ZrC NDs obtained in example 1 on the treatment of glioma in mice transplanted subcutaneously.
FIG. 7 (a) is a representative photograph of a mouse tumor of a different treatment group at the end; FIG. 7 (b) is a bar graph of the weight change of resected tumor after treatment of each treatment group; FIG. 7 (c) is a graph showing the change in average tumor volume after 808nm laser irradiation in each treatment group. Wherein, contrl is a blank control (PBS) group; NIR 808nm laser group; zrC is PVP-ZrC NDs solution injected by tail vein; zrC+NIR is a tumor group irradiated with laser at 808nm after PVP-ZrC NDs solution is injected through tail vein.
As can be seen from fig. 7 (a) to 7 (c), zrC group has an inhibitory effect on tumor growth, but the effect is not significant. The PVP-ZrC NDs solution shows obvious inhibition effect on tumor growth after being injected into tail vein and irradiated by 808nm laser (ZrC+NIR group); and compared with the Contrl group, the NIR group and the ZrC group, the ZrC+NIR group has more remarkable inhibition effect. And no death of tumor-bearing mice was observed in the zrc+nir group as continuously observed. From this, it is demonstrated that PVP-ZrC NDs obtained in example 1 have good photothermal ablation effect on solid tumors.
8. Summary analysis
The embodiment of the invention mainly uses zirconium carbide (ZrC) as a two-dimensional metal carbide, and the zirconium (Zr) is in the same family as the Ti, but has a larger period, and because of the external heavy atoms, the zirconium (Zr) can be used for optimizing the thermal plasma effect. On the basis, the method takes commercial zirconium carbide as a raw material, adopts an ultrasonic liquid phase stripping method to prepare the zirconium carbide nano-dots (ZrC NDs) with good stability and water solubility, and is modified by polyvinylpyrrolidone (PVP) to obtain the zirconium carbide nano-material (PVP-ZrC NDs) with good photo-thermal performance. The PVP-ZrC NDs prepared by the method have good near infrared light absorption and photothermal conversion capability, and can be used for tumor thermal ablation at a lower concentration. In addition, PVP-ZrC NDs also have excellent free radical scavenging ability, and can overcome inflammatory reaction caused by traditional PTT. Tumor growth of tumor-bearing mice is obviously inhibited after intravenous injection of PVP-ZrC NDs under the irradiation of near infrared laser. More importantly, these tiny PVP-ZrC NDs were not significantly toxic in vivo and efficient in vivo excretion was observed. Taken together, our findings underscore that these ultra-small PVP-ZrC NDs can eliminate tumors with the aid of near infrared lasers, and that ROS scavenging causes anti-inflammatory responses, potentially providing safer, more effective treatment for gliomas.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (5)
1. The preparation method of the two-dimensional metal carbide nanocomposite for the photothermal treatment of tumors is characterized by comprising the following steps of:
s1, adding two-dimensional metal carbide powder into a stripping solvent, carrying out ultrasonic stripping under ice water bath, centrifuging, collecting supernatant, and freeze-drying to obtain two-dimensional metal carbide nano-dots; the two-dimensional transition metal carbide is zirconium carbide; the stripping solvent is N-methyl pyrrolidone;
s2, dispersing the two-dimensional transition metal carbide nano points in ethanol, adding PVP for premixing, stirring and refluxing at 70-90 ℃ for 8-24 hours, and centrifuging to obtain a PVP modified two-dimensional metal carbide nano composite material;
in S1, the dosage ratio of the two-dimensional transition metal carbide powder to the stripping solvent is 1g: 10-30 mL;
in S1, the ultrasonic stripping power is 300W; the ultrasonic stripping time is 1-3 h;
in S2, the dosage ratio of the two-dimensional transition metal carbide nano-dots to ethanol and PVP is 500mg: 10-30 mL: 2-5 g.
2. The two-dimensional metal carbide nanocomposite prepared by the method of claim 1.
3. Use of the two-dimensional metal carbide nanocomposite of claim 2 in the preparation of a medicament for non-inflammatory photothermal treatment of tumors.
4. The use according to claim 3, wherein the two-dimensional metal carbide nanocomposite is dispersed in water to a concentration of 1-2 mg/mL.
5. The use according to claim 3, wherein the two-dimensional metal carbide nanocomposite is used for preparing photosensitizers with oxygen radical scavenging capacity.
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